The aspects of the disclosed embodiments are directed to quaternary oxycodone, oxymorphone, hydrocodone and hydromorphone ammonium compounds described in general Formula I, and to compositions and uses of said compounds for treating pain associated with a variety of chronic human disorders including for example neuropathic pain and pain associated with cancer, surgeries or injuries.
The aspects of the disclosed embodiments may be generically categorized within the class of compounds known as opioids. It is well known that opioid drugs target three types of endogenous opioid receptors (i.e., mu, delta and kappa receptors) in biological systems. Most opioids, such as morphine, are mu opioid agonists that are often used as analgesics for the treatment of severe pain due to their activation of mu opioid receptors in the brain and central nervous system (CNS). Opioid receptors are, however, not limited to the CNS, and have been found in other tissues throughout the body. A number of side effects of opioid drugs may be caused by activation of these peripheral receptors including nausea, vomiting and inhibition of normal propulsive gastrointestinal function resulting in side effects such as, for example, constipation, drowsiness, respiratory depression, changes in mood, and mental clouding without a resulting loss of consciousness. Thus, it is widely recognized that opioid treatment induced constipation is sometimes even more difficult to treat than the underlying pain. Towards this end, several ameliorating strategies have been developed which include, for example, the administration of opioid receptor antagonist such as for example, Naltrexon to patients for reversing opioid induced constipation. However, since central acting opioid receptor antagonists also reverse analgesia and precipitate opioid withdrawal symptoms, non CNS penetrant quaternary ammonium derivatives of opioid antagonist such as for example, Methyl Naltrexone have been developed and these derivatives have been shown to reverse peripheral side effects of opioids without inducing CNS mediated withdrawal symptoms or reversing analgesia. However, since use of opioid antagonists targets the amelioration of already manifested side effects, these treatment regimens add cost and burden to the treatment of pain. Accordingly there is a need for developing opioid derivatives that would exhibit reduced peripheral side-effects while maintaining central analgesic properties.
Moreover, prescription opioid use is also the subject of extensive “substance abuse” which is increasing and exacts a high toll on patients, physicians, and society. Nonmedical users of prescription pain relievers quadrupled from 1990 to 2000, with abuse of oxycodone and hydrocodone products particularly common. Extracting a societal toll, this prescription drug abuse is associated with higher rates of comorbidities and drug-related mortality.
Chronic pain affects approximately 50 million Americans each year, and an additional 48 million Americans 12 years or older have used prescription drugs for nonmedical reasons in their lifetimes. Among the most potent analgesics available, opioids have a recognized role in the treatment of cancer- and non-cancer-related chronic pain conditions. Yet many physicians, concerned that their patients will become addicted, are reluctant to prescribe these agents, contributing to the widespread undertreatment of chronic pain.
One strategy for reducing the potential for abuse is development of tamper resistant opioid formulations designed to create barriers to manipulations of prescription drug formulations. Additionally, opioid formulations incorporating pharmacological strategies have also been designed to deter or resist misuse and abuse by making it difficult to achieve euphoria through opioid use. As pharmacologically proactive tools, these formulations use either pharmacodynamic or physical mechanisms to make opioids unattractive to individuals who abuse them, as well as present barriers to unintentional or deliberate misuse. Such formulations are currently available and have had mixed epidemiological results. New compounds and formulations that obviate the limitations of existing therapeutics are thus needed.
Pharmaceutical strategies have been developed as either agonist-antagonist or agonist-additional active ingredient combinations. Agonist-antagonist formulations can be considered pharmacodynamic strategies because they act to reduce reward at the receptor level. An example of such a strategy is Embeda (Pfizer), which combines morphine with an antagonist such as naltrexone. If this formulation is ingested normally, the naltrexone remains latent; if it is crushed, the naltrexone is released and reduces the effects of the morphine Other agonist-antagonist combinations include Talwin containing pentazocine hydrochloride and naloxone hydrochloride equivalent; Valoron a combination of tilidine and naloxone; and Terngesic a combination of buprenorphine and naloxone. These strategies cause, in some instances, opioid withdrawal symptoms.
Opioids with a reduced side effect and abuse potential are one of the most important unmet needs in the management of chronic pain and help physicians to better balance optimal analgesia with reduced risk of having to treat either opioid induced side effects or worry about prescription misuse and abuse.
Compounds of the disclosed embodiments combine agonist/antagonist activity at opioid receptors in a single molecular entity and exploit (as principle of their pharmacological action) relative drug distribution/partitioning differences between agonist and quaternary ammonium antagonist in peripheral and central nervous system compartments, thereby reducing peripheral side effects associated with opioid receptor agonist use (such asGI effects, or respiratory depression and pruritis). In addition, by controlling the delivery of a centrally acting analgesic opioid through the rate of enzymatic conversion of a peripheral quaternary ammonium opioid antagonist, compounds of the disclosed embodiments are abuse-resistant while maintaining analgesic properties of the parent opioid.